The foundations of immune checkpoint blockade and the ipilimumab approval decennial

Cancer immunity, and the potential for cancer immunotherapy, have been topics of scientific discussion and experimentation for over a hundred years. Several successful cancer immunotherapies — such as IL-2 and interferon-α (IFNα) — have appeared over the past 30 years. However, it is only in the past decade that immunotherapy has made a broad impact on patient survival in multiple high-incidence cancer indications. The emergence of immunotherapy as a new pillar of cancer treatment (adding to surgery, radiation, chemotherapy and targeted therapies) is due to the success of immune checkpoint blockade (ICB) drugs, the first of which — ipilimumab — was approved in 2011. ICB drugs block receptors and ligands involved in pathways that attenuate T cell activation — such as cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1) and its ligand, PDL1 — and prevent, or reverse, acquired peripheral tolerance to tumour antigens. In this Review we mark the tenth anniversary of the approval of ipilimumab and discuss the foundational scientific history of ICB, together with the history of the discovery, development and elucidation of the mechanism of action of the first generation of drugs targeting the CTLA4 and PD1 pathways.